Many drug delivery systems (DDSs) including chemical enhancers, electric fields, ultrasound and thermal methods have been challenged to increase the skin permeability of poorly-absorbable drugs like insulin through the percutaneous route. [1][2][3][4][5] However, the success of these transdermal DDSs has been limited because of the strong barrier function of the skin i.e. low membrane permeability of drugs through the skin. However, micron-scale needles including micropiles made of stainless steel showed an increase of the transdermal permeability of drugs. [6][7][8] Among them, the permeability of insulin through the skin was dramatically increased in rats. 9)However, these microneedles are made of iron, i.e. stainless steel, there is a possibility of side effect like metallic allergy.On the other hand, we have been studying a new delivery system, self-dissolving micropiles (SDMP), for the percutaneous administration of macromolecular drugs using threadforming biopolymers such as dextrin and chondroitin sulfate. These polymers were used as a base polymer of SDMP. Dextrin was used for the base polymer of insulin SDMP in mice study.10) However, there were some problems in fragility as a SDMP. Chondroitin sulfate could keep the viscosity in a SDMP and was selected as a base polymer because of the hardness and sharpness of the top of SDMP.11) In our feasibility studies using mice and rats, insulin, human growth hormone (hGH) and erythropoietin (EPO) were used as representatives of peptide/protein drugs. 10,11) With insulin, the efficiency was evaluated by measuring the hypoglycemic effect of insulin after administration of insulin SDMP to mice. The pharmacological availability (PA) of SDMP was over 90% as compared to intravenously injected insulin solution.10) Also, SDMP containing EPO and hGH showed high bioavailabilities (BA) of EPO, 80-90%, after percutaneous administration to mice and rats.11) Through these proof-of-concept (POC) experiments, SDMP was found out to be useful for the percutaneous administration of peptide/protein drugs. Although the POC experiments were performed in small animals, the results cannot be directly applied to human, i.e. patients. Therefore, as a second step of the POC study, insulin SDMP was prepared and its pharmacological availability has been studied in large animal, beagle dogs, in relation to the oral glucose tolerance test (OGTT). ExperimentalMaterials Insulin sodium salt was prepared from bovine pancreas insulin (25 IU/mg) in our laboratory.12) Glucose CII-Test kit was purchased from Wako Pure Chemical Industries, Ltd. (Osaka, Japan). D-(ϩ)-Glucose and chondroitin sulfate were obtained from Nacalai Tesque, Ltd. (Kyoto, Japan). Male beagle dogs, 10.2-12.6 kg, were obtained from Nippon SLC Co., Ltd. (Hamamatsu, Japan). All other materials used were of reagent grade and were used as received.Preparation of Insulin Micropiles To 8.0 or 4.0 mg of sodium insulin, 60 ml of 0.1 M phosphate buffered saline (PBS, pH 7.4) was added and completely dissolved. By adding 92 mg of chondroiti...
Microparticles-adsorbed insulin and zinc insulin (PenfilN) were molded to self-dissolving micropiles (SDMPs) with chondroitin sulfate as the base for the percutaneous administration of insulin. Porous silicon dioxide (Sylysia 320, 440 and 730) and porous calcium silicate (FloriteRE) were used as microparticles. As a reference, insulin loaded SDMPs were prepared. SDMPs were percutaneously administered to mice at the insulin dose level of 2.5 IU/kg. After the insertion of SDMPs to mouse skin, blood samples were collected for 8 h and plasma glucose levels were measured. There were not significant differences on minimum plasma glucose levels between the test preparations. However, T(mins), the time when the minimum glucose level appeared were 1.5 +/- 0.2 h (Sylysia 320), 1.3 +/- 0.2 h (Sylysia 440), 1.6 +/- 0.4 h (Sylysia 730), 2.1 +/- 0.3 h (Florite) and 1.7 +/- 0.3 h (zinc insulin) which were greater than insulin SDMP, 0.8 +/- 0.1 h. In addition, greater hypoglycemic effects were observed with SDMPs containing adsorbent-insulin and/or zinc insulin than insulin SDMP. The mean AACs (area above the plasma glucose level vs. time curve) of SDMPs containing adsorbent-insulin and zinc insulin were 357.8% h for FloriteRE, 333.1% h for Sylysia 320, 308.1% h for Sylysia 440, 328.1% h for Sylysia 730, and 374.7% h for zinc insulin, respectively, which were about two folds higher than that of insulin SDMN, 161.2% h. Those results suggest the usefulness of SDMPs composed of adsorbent-insulin as a long-acting percutaneous insulin preparation.
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